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FDA Approves Tafinlar

FDA Approves Tafinlar (dabrafenib) for Advanced Melanoma

May 29, 2013 -- GlaxoSmithKline plc announced today that the U.S. Food and Drug Administration (FDA) has approved Tafinlar (dabrafenib). Tafinlar is indicated as a single-agent oral treatment for unresectable melanoma (melanoma that cannot be removed by surgery) or metastatic melanoma (melanoma which has spread to other parts of the body) in adult patients with BRAF V600E mutation. Tafinlar is not indicated for the treatment of patients with wild-type BRAF melanoma. The mutation must be detected by an FDA-approved test, such as the companion diagnostic assay from bioMérieux S.A., THxID™-BRAF.

Among those with metastatic melanoma, approximately half have a BRAF mutation, which is an abnormal change in a gene that can enable some melanoma tumours to grow and spread.[i]

Tafinlar is approved for patients with the BRAF V600E mutation, which accounts for approximately 85 percent of all BRAF V600 mutations in metastatic melanoma.[ii]

As part of the FDA approval, which was based on clinical studies evaluating the efficacy and safety, warnings and precautions were also identified. Dabrafenib can cause serious side effects, some of which can be life threatening, including increasing the risk of developing new primary cutaneous malignancies (new skin cancers), tumour promotion in BRAF wild-type melanoma, serious febrile drug reactions (severe fevers), hyperglycemia (blood sugar problems), uveitis and iritis (severe eye problems), hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and embryofetal toxicity (potential harm to the unborn baby in pregnant women).

GSK will be making Tafinlar available for prescription no later than in the early third quarter of 2013.

In 2010, GSK entered a collaboration with bioMérieux to develop a companion diagnostic test to detect BRAF V600 (V600E and V600K) gene mutations found in several cancers, including melanoma. bioMérieux has received FDA pre-market approval of THxID™-BRAF. Currently, it is the only FDA-approved test that detects the V600K mutation.

Tafinlar (dabrafenib) Clinical Data

The approval of dabrafenib is based on results from one multicenter, international trial, specifically the pivotal, open-label Phase III BREAK-3 study that randomised 250 previously untreated adult patients with BRAF V600E mutation-positive unresectable or metastatic melanoma to receive dabrafenib or dacarbazine (chemotherapy) in a 3:1 ratio, respectively. The primary endpoint was progression-free survival (PFS) as assessed by the investigator. Other pre-specified endpoints included independent radiology review committee (IRRC) assessed PFS, confirmed objective response rate (ORR) and duration of response. Twenty-eight patients (44%) crossed over from the dacarbazine arm at the time of disease progression to receive dabrafenib.

The study demonstrated a statistically significant increase in PFS in patients treated with dabrafenib, compared to dacarbazine (HR=0.33; [95% CI: 0.20, 0.54], p<0.0001). The median PFS was 5.1 months with dabrafenib (95% CI: 4.9, 6.9) compared to 2.7 months with dacarbazine (95% CI: 1.5, 3.2). The ORR with dabrafenib was 52 percent (95% CI: 44, 59) versus 17 percent with dacarbazine (95% CI: 9, 29).

In this study, the most common adverse reactions (greater than or equal to 10%) of any grade for dabrafenib included hyperkeratosis (thickening of the outer layer of the skin) (37%), headache (32%), pyrexia (fever) (28%), arthralgia (joint aches) (27%), papilloma (warts) (27%), alopecia (hair loss) (22%), palmar-plantar erythrodysesthesia (redness, swelling, peeling or tenderness of hands or feet) (20%), rash (17%), back pain (12%), cough (12%), myalgia (muscle aches) (11%), constipation (11%) and nasopharyngitis (cold-like symptoms) (10%).

Dabrafenib was also prospectively evaluated in adult patients with BRAF V600E mutation-positive melanoma, metastatic to the brain. The single-arm, open-label Phase II trial enrolled patients into two cohorts. Patients in Cohort A (n=74) had received no prior local therapy for brain metastases, while patients in Cohort B (n=65) had received at least one local therapy for brain metastases, including but not limited to surgical resection, whole brain radiotherapy or stereotactic radiosurgery such as gamma knife, linear-accelerated-based radiosurgery, charged particles or CyberKnife. In addition, patients in Cohort B were required to have evidence of disease progression in a previously treated lesion or an untreated lesion. Additional eligibility criteria were at least one measurable lesion of 0.5 cm or greater in largest diameter on contrast-enhanced MRI, stable or decreasing corticosteroid dose, and no more than two prior systemic regimens for treatment of metastatic disease.

The primary outcome measure was the estimation of the overall intracranial response rate (OIRR) in each cohort. The OIRR for Cohort A was 18 percent (95% CI: 9.7, 28.2). For Cohort B, the OIRR was also 18 percent (95% CI: 9.9, 30.0). The median duration of response was 4.6 months (95% CI: 2.8, Not Reached) and 4.6 months (95% CI: 1.9, 4.6) in Cohort A and Cohort B, respectively.

About Melanoma and Metastatic Melanoma

Melanoma is the most serious and deadly form of skin cancer.[iii] According to statistics from the National Cancer Institute, in 2013 there will be an estimated 9,480 deaths resulting from melanoma in the United States.[iv] When melanoma spreads in the body, the disease is called metastatic melanoma.[v] Approximately half of all people with metastatic melanoma have a BRAF mutation, which is an abnormal change in a gene that can enable some melanoma tumours to grow and spread.[ii] One in two patients worldwide with metastatic melanoma is expected to survive for a year after diagnosis,[vi] while in the U.S., the five-year survival rate was 16 percent (2003-2009).[vii] The median age of a newly diagnosed metastatic melanoma patient is almost a decade younger than other cancers.[viii]

About Tafinlar (dabrafenib)

Tafinlar (dabrafenib) is now approved for the treatment of adult patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of use: Tafinlar is not recommended for use in patients with wild-type BRAF melanoma.

Tafinlar is not approved or licensed in Europe and may not be approved in other parts of the world for the treatment of patients with BRAF V600 mutation-positive unresectable melanoma or metastatic melanoma.

Important Safety Information for Tafinlar (dabrafenib)


New Primary Cutaneous Malignancies Tafinlar (dabrafenib) results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma and melanoma. In the pivotal trial of dabrafenib, cuSCC occurred in 7% (14/147) of patients treated with dabrafenib and in none of the patients treated with dacarbazine. Across clinical trials of dabrafenib (n=586), the incidence of cuSCC was 11%. The median time to first cuSCC was 9 weeks (range: 1 to 53 weeks). Of those, patients who developed a cuSCC, approximately 33% developed one or more cuSCC with continued dabrafenib. The median time between diagnosis of the first cuSCC and the second cuSCC was 6 weeks.

In the pivotal trial of dabrafenib, the incidence of new primary malignant melanomas was 2% (3/187) for patients receiving dabrafenib while no chemotherapy-treated patient was diagnosed with new primary malignant melanoma.

Tumour Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors.

Serious Febrile Drug Reactions In the pivotal trial of Tafinlar (dabrafenib), serious febrile drug reactions, defined as serious cases of fever or fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure in the absence of another identifiable cause (e.g., infection) occurred in 3.7% (7/187) of patients treated with dabrafenib and in none of the patients treated with dacarbazine. The incidence of fever (serious and non-serious) was 28% in patients treated with dabrafenib and 10% in patients treated with dacarbazine. In patients treated with dabrafenib, the median time to initial onset of fever (any severity) was 11 days (range: 1 to 202 days), and the median duration of fever was 3 days (range 1 to 129 days).

Hyperglycemia Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycemic agent therapy, can occur with Tafinlar (dabrafenib). In the pivotal trial of dabrafenib, 5 of 12 patients with a history of diabetes required more intensive hypoglycemic therapy while taking dabrafenib. The incidence of Grade 3 hyperglycemia based on laboratory values was 6% (12/187) in patients treated with dabrafenib compared to none of the dacarbazine-treated patients.

Uveitis and Iritis Uveitis (including iritis) occurred in 1% (6/586) of patients treated with Tafinlar (dabrafenib) across clinical trials.

Glucose-6-Phosphate Dehydrogenase Deficiency Tafinlar (dabrafenib), which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.

Embryofetal Toxicity Based on its mechanism of action, Tafinlar (dabrafenib) can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose.

Most Common Adverse Reactions The most common adverse reactions (greater than or equal to 10%) of any grade included hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%), papilloma (27%), alopecia (22%), palmar-plantar erythrodysesthesia (20%), rash (17%), back pain (12%), cough (12%), constipation (11%), myalgia (11%), and nasopharyngitis (10%).

The most common serious adverse reactions (greater than or equal to 2%) of grades 3 and 4 include cuSCC (4%), back pain (3%), pyrexia (3%), constipation (2%), and palmar-plantar erythrodysesthesia (2%).

Drug Interactions

Effects of Other Drugs on Dabrafenib

Drugs that Inhibit or Induce Drug-Metabolising Enzymes: Dabrafenib is primarily metabolised by CYP2C8 and CYP3A4. Strong inhibitors or inducers of CYP3A4 or CYP2C8 may increase or decrease, respectively, concentrations of dabrafenib.

Drugs that Affect Gastric pH: Drugs that alter the pH of the upper GI tract (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic exposure of dabrafenib.

Effects of Dabrafenib on Other Drugs

Dabrafenib induces CYP3A4 and may induce other enyzmes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UDP glucuronosyltransferases (UGT) and may induce transporters. Dabrafenib decreased the maximum concentration (Cmax) and area under the curve (AUC) of midazolam (a substrate of CYP3A4) by 61% and 74%, respectively. Coadministration of Tafinlar with other substrates of these enzymes, including warfarin, dexamethasone, or hormonal contraceptives, can result in decreased concentrations and loss of efficacy.

Females and Males of Reproductive Potential Tafinlar (dabrafenib) may impair fertility in males.


[i] Flaherty KT, Robert C, Hersey P, et al. Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. NEJM. 2012;367:107-14.

[ii] Hong DS, Vence L, Falchook G, et al. BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clin Cancer Res. 2012;18:2326–35.

[iii] Skin Cancer Foundation. “What Is Melanoma?” May 2013. Available at:

[iv] National Cancer Institute. “Melanoma.” May 2013. Available at:

[v] Melanoma Research Foundation. “Staging Melanoma.” May 2013. Available at:

[vi] Tas, Faruk. Metastatic Behavior in Melanoma: Timing, Pattern, Survival, and Influencing Factors. Jour Oncology. 2012.

[vii] SEER Stat Fact Sheets: Melanoma of the Skin. The Surveillance, Epidemiology, and End Results (SEER). May 2013. Available at:

[viii] Brady MS, Kaushal A, Ko C. “Melanoma and Other Skin Cancers.” Cancer Network. 14th Ed. March 2013. Available at:

Source: GlaxoSmithKline

Posted: May 2013

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Tafinlar (dabrafenib) FDA Approval History

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